tbuckley/cabot-search huggingface dataset:
ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients
Authors: Peter S. Cunningham, Gareth B. Kitchen, Callum Jackson, Stavros Papachristos, Thomas Springthorpe, David van Dellen, Julie Gibbs, Timothy W. Felton, Anthony J. Wilson, Jonathan Bannard-Smith, Martin K. Rutter, Thomas House, Paul Dark, Titus Augustine, Ozgur E. Akman, Andrew L. Hazel, John F. Blaikley
Journal: Journal of Clinical Investigation (2022)

BackgroundAssessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.MethodsWe present ClinCirc. This method combines 2 existing mathematical methods (Lomb-Scargle periodogram and cosinor) sequentially and is designed to measure circadian oscillations from infrequently sampled clinical data. The accuracy of this method was compared against 9 other methods using simulated and frequently sampled biological data. ClinCirc was then evaluated in 13 intensive care unit (ICU) patients as well as in a separate cohort of 29 kidney-transplant recipients. Finally, the consequences of circadian alterations were investigated in a retrospective cohort of 726 kidney-transplant recipients.ResultsClinCirc had comparable performance to existing methods for analyzing simulated data or clock transcript expression of healthy volunteers. It had improved accuracy compared with the cosinor method in evaluating circadian parameters in PER2:luc cell lines. In ICU patients, it was the only method investigated to suggest that loss of circadian oscillations in the peripheral oscillator was associated with inflammation, a feature widely reported in animal models. Additionally, ClinCirc was able to detect other circadian alterations, including a phase shift following kidney transplantation that was associated with the administration of glucocorticoids. This phase shift could explain why a significant complication of kidney transplantation (delayed graft dysfunction) oscillates according to the time of day kidney transplantation is performed.ConclusionClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.FundingUK Research and Innovation (UKRI), National Institute of Health Research (NIHR), Engineering and Physical Sciences Research Council (EPSRC), National Institute on Academic Anaesthesia (NIAA), Asthma+Lung UK, Kidneys for Life.
Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology
Authors: Egle Kvedaraite, Paul Milne, Ahad Khalilnezhad, Marion Chevrier, Raman Sethi, Hong Kai Lee, Daniel W. Hagey, Tatiana von Bahr Greenwood, Natalia Mouratidou, Martin Jädersten, Nicole Yee Shin Lee, Lara Minnerup, Yingrou Tan, Charles-Antoine Dutertre, Nathan Benac, You Yi Hwang, Josephine Lum, Amos Hong Pheng Loh, Jessica Jansson, Karen Wei Weng Teng, Shabnam Khalilnezhad, Weili Xu, Anastasia Resteu, Hong Liang Tey, Ng Lai Guan, Anis Larbi, Shanshan Wu Howland, Henrik Arnell, Samir E. L. Andaloussi, Jorge Braier, Georgios Rassidakis, Laura Galluzzo, Andrzej Dzionek, Jan-Inge Henter, Jinmiao Chen, Matthew Collin, Florent Ginhoux
Journal: Science Immunology (2022)

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
Left Atrial Mechanical Dysfunction and the Risk for Ischemic Stroke in People Without Prevalent Atrial Fibrillation or Stroke
Authors: Ankit Maheshwari, Faye L. Norby, Riccardo M. Inciardi, Wendy Wang, Michael J. Zhang, Elsayed Z. Soliman, Alvaro Alonso, Michelle C. Johansen, Rebecca F. Gottesman, Scott D. Solomon, Amil M. Shah, Lin Yee Chen
Journal: Annals of Internal Medicine (2022)

Atrial myopathy-characterized by changes in left atrial function and size-may precede and promote atrial fibrillation (AF) and cardiac thromboembolism. In people without prior AF or stroke, whether analysis of left atrial function and size can improve ischemic stroke prediction is unknown.
Low leukocyte mitochondrial DNA abundance drives atherosclerotic cardiovascular diseases: a cohort and Mendelian randomization study
Authors: Jiao Luo, Raymond Noordam, J Wouter Jukema, Ko Willems van Dijk, Sara Hägg, Felix Grassmann, Saskia le Cessie, Diana van Heemst
Journal: Cardiovascular Research (2022)

Abstract Aim Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies. Methods and results Multivariable-adjusted Cox regression analyses were conducted in 273 619 unrelated participants of European ancestry from the UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analysed using fixed-effects models. During a median follow-up of 11.8 years, restricted cubic spline Cox regression analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios (95% confidence interval) from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively. Conclusion Our findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF.
Clinical Images: Optic perineuritis in relapsing granulomatosis with polyangiitis
Authors: Ole Hudowenz, Peter Lamprecht
Journal: Arthritis & Rheumatology (2022)

The patient, a 76-year-old man who was previously diagnosed as having granulomatosis with polyangiitis (GPA) and was receiving rituximab maintenance therapy every 6 months, presented with malaise, night sweat, transient lockjaw, and right-sided facial pain and swelling following dental extraction 2 weeks earlier. He subsequently developed retrobulbar pain, conjunctival injection, chemosis, and fluctuating visual impairment. T1-weighted contrast magnetic resonance imaging (MRI) of the orbit revealed contrast enhancement of the right optic nerve sheath sparing the optic nerve itself (“doughnut sign”) consistent with optic perineuritis (coronal image in A; axial image in B). Laboratory evaluation showed elevated C-reactive protein (276 mg/liter) and leukocytosis (13,430/μl) (Supplementary Table 1, http://onlinelibrary.wiley.com/doi/10.1002/art.42426). Blood cultures and cerebrospinal fluid analysis including mycobacterial and fungal polymerase chain reaction showed no evidence of infection. Moreover, empirical antibiotic therapy did not result in clinical improvement. In GPA, optic neuropathy accompanied by retrobulbar pain and/or oculomotor nerve palsy usually occurs as a result of compression by inflammatory orbital masses (1, 2). However, it may rarely be encountered due to posterior ischemic neuropathy, optic neuritis, and/or perineuritis without inflammatory pseudotumor (1). Imaging may reveal signs of pachymeningitis, often subtle, and additional orbital apex infiltration (1-3). In some patients, high levels of inflammation markers can be detected (1, 2). Optic perineuritis has a poor prognosis with frequent recurrence of symptoms following reduction of glucocorticoid dose, thus requiring aggressive immunosuppressive treatment with cyclophosphamide and/or rituximab (1, 2). In our patient, immunosuppressive therapy was switched to combined rituximab and pulse cyclophosphamide treatment with the addition of a glucocorticoid for the re-induction of remission, resulting in protracted resolution of clinical symptoms and MRI findings (Supplementary Figure 1, http://onlinelibrary.wiley.com/doi/10.1002/art.42426). Disclosure Form Supplementary Figure 1: MRI follow-up showing resolution of contrast enhancement of the right optic nerve sheath following re-induction of remission with combined rituximab and pulse cyclophosphamide treatment and addition of glucocorticoid (A coronal image, B axial image). Supplementary Table 1: Laboratory values Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials
Authors: Adem Y Dawed, Andrea Mari, Andrew Brown, Timothy J McDonald, Lin Li, Shuaicheng Wang, Mun-Gwan Hong, Sapna Sharma, Neil R Robertson, Anubha Mahajan, Xuan Wang, Mark Walker, Stephen Gough, Leen M ‘t Hart, Kaixin Zhou, Ian Forgie, Hartmut Ruetten, Imre Pavo, Pallav Bhatnagar, Angus G Jones, Ewan R Pearson, L.M. 't Hart, M. Abdalla, J. Adam, J. Adamski, K. Adragni, K.H. Allin, M. Arumugam, N. Atabaki Pasdar, T. Baltauss, K.B. Banasik, P. Baum, J.D. Bell, M. Bergstrom, J.W. Beulens, S. Bianzano, R. Bizzotto, A. Bonneford, C.A.B. Brorsson, A.A. Brown, S.B. Brunak, L. Cabrelli, R. Caiazzo, M. Canouil, M. Dale, D. Davtian, A.Y. Dawed, F.M. De Masi, N. de Preville, K.F. Dekkers, E.T. Dermitzakis, H.A. Deshmukh, C. Dings, L. Donnelly, A. Dutta, B. Ehrhardt, P.J.M. Elders, C.E.T. Engel Thomas, L. Engelbrechtsen, R.G. Eriksen, R.E. Eriksen, Y. Fan, J. Fernandez, J. Ferrer, H. Fitipaldi, I.M. Forgie, A. Forman, P.W. Franks, F. Frau, A. Fritsche, P. Froguel, G. Frost, J. Gassenhuber, G.N. Giordano, T. Giorgino, S. Gough, U. Graefe-Mody, H. Grallert, R. Grempler, L. Groeneveld, L. Groop, V.G. Gudmundsdóttir, R.G. Gupta, M. Haid, T. Hansen, T.H. Hansen, A.T. Hattersley, R.S. Haussler, A.J. Heggie, A.M. Hennige, A.V. Hill, R.W. Holl, M.-G. Hong, M. Hudson, B. Jablonka, C. Jennison, J. Jiao, J.J. Johansen, A.G. Jones, A. Jonsson, T.K. Karaderi, J. Kaye, M. Klintenberg, R.W. Koivula, T. Kokkola, A.D.M. Koopman, A Kurbasic, T. Kuulasmaa, M. Laakso, T. Lehr, H. Loftus, R.L.A Lundbye Allesøe, A. Mahajan, A. Mari, G.M. Mazzoni, M.I. McCarthy, T.J. McDonald, D. McEvoy, N. McRobert, I. McVittie, M. Mourby, P. Musholt, P Mutie, R. Nice, C. Nicolay, A.M.N. Nielsen, B.N. Nilsson, C.N. Palmer, F. Pattou, I. Pavo, E.R. Pearson, O. Pedersen, H.K.P. Pedersen, M.H. Perry, H. Pomares-Millan, A. Ramisch, S.R. Rasmussen, V. Raverdi, M. Ridderstrale, N. Robertson, R.C. Roderick, M. Rodriquez, H. Ruetten, F. Rutters, W. Sackett, N. Scherer, J.M. Schwenk, N. Shah, S. Sharma, I. Sihinevich, N.B. Sondertoft, H. Staerfeldt, B. Steckel-Hamann, H. Teare, M.K. Thomas, E.L. Thomas, H.S. Thomsen, B. Thorand, C.E. Thorne, J. Tillner, A.T.L. Troen Lundgaard, M. Troll, K.D.T. Tsirigos, A. Tura, M. Uhlen, N. van Leeuwen, S. van Oort, H. Verkindt, H. Vestergaard, A. Viñuela, J.K Vogt, P.W.S Wad Sackett, D. Wake, M. Walker, A. Wesolowska-Andersen, B. Whitcher, M.W. White, H. Wu
Journal: The Lancet Diabetes & Endocrinology (2022)
Aortic stenosis and the haemostatic system
Authors: Antonin Trimaille, Sandy Hmadeh, Kensuke Matsushita, Benjamin Marchandot, Gilles Kauffenstein, Olivier Morel
Journal: Cardiovascular Research (2022)

Abstract Aortic stenosis (AS) affects more than 10% of the population over 80 years of age and constitutes a major risk factor for heart failure, thromboembolic stroke, and death. A better understanding of the disease, including its interaction with the haemostatic system, is a prerequisite to develop prophylactic treatments. AS pathogenesis is a dynamic process involving endothelial dysfunction, inflammation, fibrosis, and calcification. Several studies support the interplay between the components of the haemostatic system such as platelets, the coagulation system, von Willebrand factor, and extracellular micro-particles at each pathophysiological stage of AS. Previous reports have evidenced persistent biological activity of the native valve after transcatheter aortic valve replacement and the subsequent development of microthrombosis that may impact the function of the newly implanted valve. Here, we review the current evidence on the interplay between AS and prothrombotic activity, and we emphasize the clinical consequences of these interactions after aortic valve replacement.
Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children
Authors: Qin Xu, Pedro Milanez-Almeida, Andrew J. Martins, Andrea J. Radtke, Kenneth B. Hoehn, Cihan Oguz, Jinguo Chen, Can Liu, Juanjie Tang, Gabrielle Grubbs, Sydney Stein, Sabrina Ramelli, Juraj Kabat, Hengameh Behzadpour, Maria Karkanitsa, Jacquelyn Spathies, Heather Kalish, Lela Kardava, Martha Kirby, Foo Cheung, Silvia Preite, Patrick C. Duncker, Moses M. Kitakule, Nahir Romero, Diego Preciado, Lyuba Gitman, Galina Koroleva, Grace Smith, Arthur Shaffer, Ian T. McBain, Peter J. McGuire, Stefania Pittaluga, Ronald N. Germain, Richard Apps, Daniella M. Schwartz, Kaitlyn Sadtler, Susan Moir, Daniel S. Chertow, Steven H. Kleinstein, Surender Khurana, John S. Tsang, Pamela Mudd, Pamela L. Schwartzberg, Kalpana Manthiram
Journal: Nature Immunology (2022)
Response to “Intrathecal trastuzumab: What else do we need to consider?” by Gao et al.
Authors: Émilie Le Rhun, Florence Oberkampf, Claire Bonneau
Journal: Neuro-Oncology (2022)

Journal Article Response to “Intrathecal trastuzumab: What else do we need to consider?” by Gao et al. Get access Émilie Le Rhun, Émilie Le Rhun Departments of Neurology and Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar Florence Oberkampf, Florence Oberkampf Hemato-oncology Unit, Alpes-Leman Hospital (CHAL), Contamine-sur-Arve, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Claire Bonneau Claire Bonneau Department of Surgery, Institut Curie-St Cloud, Saint Cloud, FranceINSERM U900, Institut Curie-St Cloud, Saint Cloud, France Corresponding Author: Dr Claire Bonneau, MD, PhD, Institut Curie-Saint-Cloud, Department of surgery, 35 rue Dailly, 92210 Saint Cloud, France (claire.bonneau@curie.fr). https://orcid.org/0000-0001-6251-286X Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 2, February 2023, Pages 420–421, https://doi.org/10.1093/neuonc/noac258 Published: 19 December 2022 Article history Corrected and typeset: 19 December 2022 Published: 19 December 2022
Interferon-γ drives macrophage reprogramming, cerebrovascular remodelling, and cognitive dysfunction in a zebrafish and a mouse model of ion imbalance and pressure overload
Authors: Dilem C Apaydin, Bhakti I Zakarauskas-Seth, Lorenzo Carnevale, Onur Apaydin, Marialuisa Perrotta, Raimondo Carnevale, Maria P Kotini, Ilan Kotlar-Goldaper, Heinz-Georg Belting, Daniela Carnevale, Alessandro Filosa, Suphansa Sawamiphak
Journal: Cardiovascular Research (2022)

Abstract Aims Dysregulated immune response contributes to inefficiency of treatment strategies to control hypertension and reduce the risk of end-organ damage. Uncovering the immune pathways driving the transition from the onset of hypertensive stimulus to the manifestation of multi-organ dysfunction are much-needed insights for immune targeted therapy. Methods and results To aid visualization of cellular events orchestrating multi-organ pathogenesis, we modelled hypertensive cardiovascular remodelling in zebrafish. Zebrafish larvae exposed to ion-poor environment exhibited rapid angiotensinogen up-regulation, followed by manifestation of arterial hypertension and cardiac remodelling that recapitulates key characteristics of incipient heart failure with preserved ejection fraction. In the brain, time-lapse imaging revealed the occurrence of cerebrovascular regression through endothelial retraction and migration in response to the ion-poor treatment. This phenomenon is associated with macrophage/microglia-endothelial contacts and endothelial junctional retraction. Cytokine and transcriptomic profiling identified systemic up-regulation of interferon-γ and interleukin 1β and revealed altered macrophage/microglia transcriptional programme characterized by suppression of innate immunity and vasculo/neuroprotective gene expression. Both zebrafish and a murine model of pressure overload-induced brain damage demonstrated that the brain pathology and macrophage/microglia phenotypic alteration are dependent on interferon-γ signalling. In zebrafish, interferon-γ receptor 1 mutation prevents cerebrovascular remodelling and dysregulation of macrophage/microglia transcriptomic profile. Supplementation of bone morphogenetic protein 5 identified from the transcriptomic approach as a down-regulated gene in ion-poor-treated macrophages/microglia that is rescued by interferon-γ blockage, mitigated cerebral microvessel loss. In mice subjected to transverse aortic constriction-induced pressure overload, typically developing cerebrovascular injury, neuroinflammation, and cognitive dysfunction, interferon-γ neutralization protected them from blood–brain barrier disruption, cerebrovascular rarefaction, and cognitive decline. Conclusions These findings uncover cellular and molecular players of an immune pathway communicating hypertensive stimulus to structural and functional remodelling of the brain and identify anti-interferon-γ treatment as a promising intervention strategy capable of preventing pressure overload-induced damage of the cerebrovascular and nervous systems.
Dose optimization during drug development: whether and when to optimize
Authors: Edward L Korn, Jeffrey A Moscow, Boris Freidlin
Journal: JNCI Journal of the National Cancer Institute (2022)

The goal of dose optimization during drug development is to identify a dose that preserves clinical benefit with optimal tolerability. Traditionally, the maximum tolerated dose in a small phase I dose escalation study is used in the phase II trial assessing clinical activity of the agent. Although it is possible that this dose level could be altered in the phase II trial if an unexpected level of toxicity is seen, no formal dose optimization has routinely been incorporated into later stages of drug development. Recently it has been suggested that formal dose optimization (involving randomly assigning patients between 2 or more dose levels) be routinely performed early in drug development, even before it is known that the experimental therapy has any clinical activity at any dose level. We consider the relative merits of performing dose optimization earlier vs later in the drug development process and demonstrate that a considerable number of patients may be exposed to ineffective therapies unless dose optimization is delayed until after clinical activity or benefit of the new agent has been established. We conclude that patient and public health interests may be better served by conducting dose optimization after (or during) phase III evaluation, with some exceptions when dose optimization should be performed after activity shown in phase II evaluation.
A hepatocyte-targeting nanoparticle for enhanced hepatobiliary magnetic resonance imaging
Authors: Huan Zhang, Yingkun Guo, Ju Jiao, Ying Qiu, Yuqing Miao, Yuan He, Zhenlin Li, Chunchao Xia, Li Li, Jing Cai, Ke Xu, Xiaoli Liu, Ce Zhang, Boon-Huat Bay, Shijie Song, Yanlian Yang, Mingli Peng, Yaoyu Wang, Haiming Fan
Journal: Nature Biomedical Engineering (2022)
Cholesterol accumulation in macrophages drives NETosis in atherosclerotic plaques via IL-1β secretion
Authors: Mustafa Yalcinkaya, Panagiotis Fotakis, Wenli Liu, Kaori Endo-Umeda, Huijuan Dou, Sandra Abramowicz, Tong Xiao, Peter Libby, Nan Wang, Alan R Tall, Marit Westerterp
Journal: Cardiovascular Research (2022)

Abstract Aims Neutrophil extracellular trap formation (NETosis) increases atherosclerotic plaque vulnerability and athero-thrombosis. However, mechanisms promoting NETosis during atherogenesis are poorly understood. We have shown that cholesterol accumulation due to myeloid cell deficiency of the cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/G1) promotes NLRP3 inflammasome activation in macrophages and neutrophils and induces prominent NETosis in atherosclerotic plaques. We investigated whether NETosis is a cell-intrinsic effect in neutrophils or is mediated indirectly by cellular crosstalk from macrophages to neutrophils involving IL-1β. Methods and results We generated mice with neutrophil or macrophage-specific Abca1/g1 deficiency (S100A8CreAbca1fl/flAbcg1fl/fl or CX3CR1CreAbca1fl/flAbcg1fl/fl mice, respectively), and transplanted their bone marrow into low-density lipoprotein receptor knockout mice. We then fed the mice a cholesterol-rich diet. Macrophage, but not neutrophil Abca1/g1 deficiency activated inflammasomes in macrophages and neutrophils, reflected by caspase-1 cleavage, and induced NETosis in plaques. NETosis was suppressed by administering an interleukin (IL)-1β neutralizing antibody. The extent of NETosis in plaques correlated strongly with the degree of neutrophil accumulation, irrespective of blood neutrophil counts, and neutrophil accumulation was decreased by IL-1β antagonism. In vitro, IL-1β or media transferred from Abca1/g1-deficient macrophages increased NETosis in both control and Abca1/Abcg1 deficient neutrophils. This cell-extrinsic effect of IL-1β on NETosis was blocked by an NLRP3 inhibitor. Conclusion These studies establish a new link between inflammasome-mediated IL-1β production in macrophages and NETosis in atherosclerotic plaques. Macrophage-derived IL-1β appears to increase NETosis both by increasing neutrophil recruitment to plaques and by promoting neutrophil NLRP3 inflammasome activation.